Cryptosporidium parvum-induced ileo-caecal adenocarcinoma and WNT signaling in a rodent model

Sadia Benamrouz,Colette Creusy,Baptiste Delaire,Tony Lefebvre,Marleen Praet,Claude Cuvelier,Karine Guyot,Thierry Chassat,Renaud Blervaque,Anthony Mouray,Vanessa Dehennaut,Gabriela Certad,Marwan Osman,Nathalie Goetinck,Christian Slomianny,Christophe Audebert,Sophie Gazzola,Valérie Conseil ,Eduardo Dei‐Cas ,Nausicâa Gantois ,Magali Chabé ,Éric Viscogliosi

doi:10.1242/dmm.013292

Abstract

Cryptosporidium species are apicomplexan protozoans that are found worldwide. These parasites constitute a large risk to human and animal health. They cause self-limited diarrhea in immunocompetent hosts and a life-threatening disease in immunocompromised hosts. Interestingly, Cryptosporidium parvum has been related to digestive carcinogenesis in humans. Consistent with a potential tumorigenic role of this parasite, in an original reproducible animal model of chronic cryptosporidiosis based on dexamethasone-treated or untreated adult SCID mice, we formerly reported that C. parvum (strains of animal and human origin) is able to induce digestive adenocarcinoma even in infections induced with very low inoculum. The aim of this study was to further characterize this animal model and to explore metabolic pathways potentially involved in the development of C. parvum-induced ileo-caecal oncogenesis. We searched for alterations in genes or proteins commonly involved in cell cycle, differentiation or cell migration, such as β-catenin, Apc, E-cadherin, Kras and p53. After infection of animals with C. parvum we demonstrated immunohistochemical abnormal localization of Wnt signaling pathway components and p53. Mutations in the selected loci of studied genes were not found after high-throughput sequencing. Furthermore, alterations in the ultrastructure of adherens junctions of the ileo-caecal neoplastic epithelia of C. parvum-infected mice were recorded using transmission electron microscopy. In conclusion, we found for the first time that the Wnt signaling pathway, and particularly the cytoskeleton network, seems to be pivotal for the development of the C. parvum-induced neoplastic process and cell migration of transformed cells. Furthermore, this model is a valuable tool in understanding the host-pathogen interactions associated with the intricate infection process of this parasite, which is able to modulate host cytoskeleton activities and several host-cell biological processes and remains a significant cause of infection worldwide.

Highlights

Cryptosporidium species are apicomplexan parasitic protists that exist worldwide
Observed lesions varied from lowgrade intraepithelial neoplasia (LGIEN) to well-differentiated invasive adenocarcinoma
In eight out of 19 animals, we discovered exophytic adenomas that showed an increasing architectural distortion, glandular crowding and major cellular atypias [high-grade intraepithelial neoplasia (HGIEN)]

Summary

Introduction

The infection results from the ingestion of Cryptosporidium oocysts through the consumption of food or water that has been contaminated with fecal matter, or through direct person-to-person or animal-to-person contact (Chalmers and Katzer, 2013). This ubiquitous, intracellular parasite constitutes a large health risk to humans and animals. The ingestion of as few as ten oocysts can cause infection in immunocompetent persons (Okhuysen et al, 1999) This low infection threshold, together with the well-known resistance of Cryptosporidium oocysts to chlorine disinfection at concentrations typically applied in drinking-water plants, facilitates the waterborne transmission of cryptosporidiosis (Rowan, 2011; Yoder and Beach, 2010)

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